1. Field of the Invention
This invention relates to microbial processes for converting codeine to 14-hydroxycodeine and more particularly to such processes by means of culturing codeine with bacteria of the genus Streptomyces.
2. Prior Art
Codeine, morphine, and thebaine are natural alkaloid products of the opium poppy, Papaver somniferum. Thebaine is used to prepare a number of commercially important narcotic antagonists and agonist/antagonist analgesics by its chemical modification. Use of codeine and morphine as starting materials is also desirable but appropriate chemical routes for their use have not yet been perfected. A major requirement for the use of these three opium alkaloids for the production of some analgesics and/or narcotic antagonists is the addition of a hydroxyl group in the C-14 position. The present invention provides the first known microbial process for converting codeine to 14-hydroxycodeine with yields and efficiencies of conversion to make the process commercially feasible.
Microbial conversions of alkaloids has been known for about 25 years. Tsuda et al., Microbial Transformation of Steroids and Alkaloids, 167-193, 1964, in the publication of the I. A. M. symposium on Microbiology, Institute of Applied Microbiology. (no. 6), University of Tokyo, disclose that 120 thebaine converting strains were selected from 1700 different bacterial and fungal strains tested for that ability. Most of the 120 strains were from the basidiomycetes, especially from the wood rot fungi Trametes sanguinea. Conversions of thebaine to 14-hydroxycodeinone and 14-hydroxycodeine were disclosed. Yields of the products depended on the nutrient solution used for cultivation of the organisms.
Yamada et al., Chemical and Pharmaceutical Bulletin 10, 981-984, 1962, disclose that Trametes sanguinea was unable to convert morphine or codeine to identifiable oxidation products.
Groger et al., Experentia 25, 95-96, 1969, disclose that most of 35 strains of Trametes of European origin could convert thebaine to 14-hydroxycodeinone and various other products. Detailed accounting was not disclosed; however, 14-hydroxycodeine was found only occasionally, in trace amounts.
Liras et al., Developments in Industrial Microbiology, 16, 401-405, 1975 disclose the transformation of morphine and codeine by bacteria of the genus Arthrobacter. Morphine was transformed to 14-hydroxymorphine and an unidentified product. Codeine also was transformed into two products, the minor component of which was codeinone. The major transformed product was not identified but it was not 14-hydroxycodeine, 14-hydroxycodeinone, 14-hydroxydihydrocodeinone, or norcodeine.
Liras et al., Applied Microbiology, 30, 650-656, 1975, disclose bacterial enzyme preparations from Pseudomonas testosteroni which transformed morphine in relatively low yield to 14-hydroxymorphinone and an unidentified product. The enzyme preparations converted codeine to codeinone and 14-hydroxycodeinone.
Sewell et al., Applied Microbial Biotechnology, 19, 247-251, 1984, disclose that two species of Streptomyces and several strains of the fungus Cunninghamella transformed codeine by N-demethylating the N-methylpiperidine moiety.
Rosazza et al., Journal of Medicinal Chemistry, 18, 791-794, 1975, disclose two species of Streptomyces and several other types of microorganisms that selectively cleave either the 10-methoxy or the 11-methoxy ether groups from 10,11-dimethoxyaporphine. Soybean meal was used for the cultivation of these organisms.
Kunz, D. A., Abstracts of the Annual Meeting of the American Society of Microbiology, page 247, Feb. 25, 1985, discloses that Streptomyces griseus ATCC 10137 could catalyze a 4% molar conversion of codeine into 14-hydroxycodeine and norcodeine.